Endothelin-1 (ET-1), a 21 amino acid peptide, acting at specific receptors in vascular tissues has been demonstrated to initiate such physiological responses as: decreases/increases in systemic arterial pressure, alterations in local blood distribution, renal function (i.e. formation and composition of urine, release of circulating hormones), and dilation/contraction of nonvascular smooth muscle (i.e. respiratory, gastrointestinal). In addition to these physiological roles ET-1 may also be involved in such diverse functions as inflammatory and neuromodulatory action. ET-1 regulation of cardiovascular function may play a significant role in coronary angina and cerebral vasospasm, hypertension, and atherosclerosis. The current proposal provides a plan for identification and evaluation of systemically active non-peptide antagonists of ET-1 to be developed as novel therapeutic approaches for treating any of the disorders mentioned above. Starting with an inventory of approximately 20,000 compounds, In Vitro radioligand binding and calcium mobilization assays will serve as initial screening procedures for identifying selective ET-1 antagonists. Lead structures will then be evaluated for ET-1-antagonist activity In Vivo using cardiovascular monitoring. Compounds identified during Phase I studies will provide points of departure for synthetic chemical improvements during Phase II work with continued evaluation of compounds for a cardiovascular activity as well as the development of animal models necessary to assess other potential therapeutic uses for an ET-1 antagonist.